Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies?
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REVIEW
Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies? Daniel Martin Klotz1,2,3 · Pauline Wimberger1,2,3 Received: 5 March 2020 / Accepted: 2 July 2020 © The Author(s) 2020
Abstract Purpose Ovarian cancer is the most lethal gynaecological malignancy. Despite the introduction of bevacizumab, standard chemotherapy has remained largely unchanged and the vast majority of patients will relapse within the first two years of diagnosis. However, results from recent clinical trials demonstrating clinical benefits of PARP inhibitor treatment are rapidly changing therapeutic options for many patients with ovarian cancer. Methods Given the introduction of new therapeutic options in the treatment of ovarian cancer, we critically review key clinical trials, areas of scientific research and its clinical relevance. Results Most notably, patients with BRCA1/2 mutant ovarian cancer benefit from maintenance treatment with PARP inhibitors after (complete or partial) response to platinum-based chemotherapy. Here, we discuss the mechanism of PARP inhibition, multiple drug resistance mechanisms, including BRCA reverse mutations, altered PARP expression, changes in DNA repair pathways, kinase activation and additional drug targets that may augment PARP inhibition. Conclusion Although the use of PARP inhibitors is a huge step forward, it is apparent that patients, both with and without BRCA-mutant ovarian cancer, will eventually become resistant to PARP inhibitors. Therefore, novel combination therapies may enhance PARP inhibitor efficacy and overcome resistance mechanisms. Keywords Ovarian cancer · PARP inhibitors · Drug resistance · Clinical trials · Drug targets
Introduction While being the fifth most common gynaecological malignancy, ovarian cancer is the leading cause of death from gynaecological malignancies; about 7500 women are newly diagnosed and about 5500 die from the disease in Germany each year [1]. Epithelial ovarian cancer accounts for about 90% of the disease [2], of which high-grade serous ovarian cancer (HGSOC) shows the lowest average 5-year survival rates of only about 40% for advanced stages of the disease [3, 4]. The mainstay of treatment consists of surgical * Daniel Martin Klotz [email protected] 1
Dresden and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
2
Department of Gynecology and Obstetrics, Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3
National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
debulking with macroscopic complete resection and platinum-based chemotherapy. It has been demonstrated that surgical debulking is the only modifiable prognostic factor after diagnosis of HGSOC. If macroscopic complete resection can be achieved, 5-year survival rates may improve from around 20% to up to 60% for advanced HGSOC [3]. However, most patients (80%) will relapse within the first 2 years [5]. Despite the burd
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